The present intention relates to a method for preparing 1-hydroxy-1,1-diphosphonic acid compounds.
The concept of “drug targeting”, i.e., the targeted accumulation of medicaments at the location of desired action, is a strategy that has been used for some time in medicine and the pharmaceutical industry. Of special interest in this connection is the use of cytostatic agents, for example, of N lost derivatives such as chlorambucil (4-(4-bis-(2-chloroethyl)amino)benzene butanoic acid) coupled to special alkane diphosphonic acids. As a result of the high affinity of the diphosphonic acids to apatite of the bone structure, a targeted organ specificity is obtained. The compound class of such 1-hydroxy-1,1-diphosphonic acid compounds, their manufacture as well as their use as pharmacological compositions is described in European patent EP 0 170 896 B1.
According to EP 0 170896B1,1-hydroxy-1,1-diphosphonic acid compounds are produced from carboxylic acid chlorides by reaction with H3PO3 in the presence of a dehydrating agent in yields of approximately 50%.
For the pharmaceutical use, the 1-hydroxy-1,1-diphosphonic acid compounds must have a high degree of purity; also, high yields of the manufacturing processes are desirable.
Moreover, the compounds must have a certain solubility for pharmaceutical use. The solubility of these compounds is in itself very low; moreover, the compounds are partially hydrolytically unstable. An improved solubility and thus a higher concentration in the pharmacological composition can be obtained, for example, by employing salts of the corresponding compounds. According to the prior art, the corresponding salts are produced by neutralization with the equivalent amount of the base. In this connection, the isolation of the salts is realized by precipitation with organic solvents, for example, alcohols, by crystallization, or by solvent evaporation from the (partially) neutralized solution. However, discolored products are often obtained with these methods; also, the products partially decompose resulting in a reduced yield; moreover, the partially uncharacterized decomposition products are undesirable in particular in connection with the use in the pharmaceutical sector.
For the isolation of the salts, it is proposed in DE 198 20 974 A1 to isolate the salts by means of freeze-drying.